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211: Cardiotonic steroids induce an anti-angiogenic profile in first trimester cytotrophoblast cells
www.AJOG.org
Clinical Obstetrics, Epidemiology, Fetus, Medical-Surgical Complications, Neonatology, Physiology/Endocrinology, Prematurity
CONCLUSION: Our results, in a large cohort of healthy, non-diabetic
women have shown that insulin resistance, even at levels below those diagnostic of gestational diabetes, is associated with maternal and fetal inflammatory response. These findings have important implications for defining the pathway for fetal programming of later metabolic syndrome and childhood obesity.
211 Cardiotonic steroids induce an anti-angiogenic profile in first trimester cytotrophoblast cells Jessica Ehrig1, Kelsey Kelso1, Russell Fothergill1, Steven Allen1, Richard Jones1, Thomas Kuehl1, Mohammad Uddin1 1 Scott & White Memorial Hospital / Texas A&M Health Science Center College of Medicine, Department of Obstetrics & Gynecology, Temple, TX
OBJECTIVE: Preeclampsia (preE), a hypertensive disorder unique to pregnancy, is characterized by abnormal placentation. Our investigative team has demonstrated that marinobufagenin (MBG), one of the cardiotonic steroids (CTSs), inhibits these critical steps for normal placental development: proliferation, migration and invasion of cytotrophoblast (CTB) cells. The aim of this study is to determine whether CTSs induce anti-angiogenic effects in CTB cells. STUDY DESIGN: Cells from the human extravillous CTB cell line Sw.71, derived from first trimester chorionic villus tissue, were incubated with 0.1, 1, 10, and 100 nM of each of three types of CTS (MBG, Cinobufatalin and Ouabain) for 72 h. Thereafter, the levels of angiogenic factors, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and anti-angiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEnd) were measured in the cell culture media by commercially available ELISA kits. Additionally, the expression of three CTB receptors, VEGF-1, angiogenic angiotensin type 1 receptor (AT1) and anti-angiogenic angiotensin type 2 receptor (AT2) were assayed using immunoblotting (western blot) in cell lysates. RESULTS: sFlt-1 and sEnd secretion were significantly increased while VEGF and PIGF were decreased in the culture media of CTB cells treated with ⭌1 nM of all three CTSs (*p⬍0.05 for each). The AT2 receptor expression was significantly up-regulated in ⭌ 1 nM CTStreated CTB cells, whereas AT2 and VEGF-1 receptor expressions were down-regulated (*p⬍0.05 in each case). CONCLUSION: Exposure of CTB cells to CTSs induces an anti-angiogenic profile by: (i) up-regulating AT2 receptor expression; (ii) downregulating AT1 and VEGF-1 receptor expression; (iii) increasing secretion of sFlt-1 and sEnd; and (iv) decreasing secretion of VEGF and PlGF.
212 Circulating adipokines in twins and singletons - linking the bridge from plurality to restricted fetal growth Jiga Haas1, Eyal Sivan1, Eyal Schiff1, Yoav Yinon1, Mordechai Dulitzky1, Eran Barzilay1, Rina Hemi2, Clara Pariente2, Hannah Kanety2, Shali Mazaki-Tovi1 1 Sheba Medical Center, Tel-Hashomer, Department of Obstetrics and Gynecology, Ramat Gan, Israel, 2Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Department of Obstetrics and Gynecology, Ramat Gan, Israel
OBJECTIVE: The condensational view is that the uterine milieu is limited in its ability to nurture more than one fetus. Yet, the mechanism(s) by which attenuated twins growth is achieved has eluded elucidation. Adipokines have been implicated in fetal growth and development. The aim of this study is to determine cord blood adiponectin and leptin in twins and singletons. STUDY DESIGN: This is a case-control study included 2 groups of newborns, matched for gestational age and birthweight percentile: 1. singleton (n⫽60) and 2. twins (n⫽44). Adiponectin and leptin were determined in arterial cord blood. Non-parametric and parametric statistical methods were used. RESULTS: Median adiponectin (31.5 vs. 63 g/dL) and leptin (2.5 vs. 5.6 ng/dL) concentrations was lower in twins vs. singletons (p⬍0.001 for both comparisons). Among SGA newborns, median concentra-
Poster Session I
tion of adiponectin (p⫽0.02), but not leptin (p⫽0.1), was lower in twins compared to singleton. Cord blood adiponectin was strongly correlated with gestational age (p⬍0.001, r⫽0.55) and birthweight (p⬍0.001, r⫽0.59), as was cord blood leptin (gestational age: p⫽0.005, r⫽0.27; birthweight: p⬍0.001, r⫽0.44). Regression analysis revealed that plurality, gestational age and birthweight were significantly and independently associated with cord blood adiponectin concentrations after adjustment for maternal BMI, age and gender. Similar regression model did not revealed association between plurality and cord blood leptin concentrations. CONCLUSION: Twins pregnancies are associated with lower cord blood concentrations of adiponectin, but not leptin, compared with singleton gestations. These findings suggest that alterations in adiponectin concentrations may provide a molecular mechanism to account for the growth disparity between twins and singleton. These findings support the concept that adipokines, particularly adiponectin may play a role in the complex and intriguing process of fetal growth.
213 Acute ascending aorta occlusion leads to decreased cerebral perfusion pressure in a fetal sheep Heikki Huhta1, Juha Räsänen4, Juulia Junno1, Mervi Haapsamo1, Tiina Erkinaro2, Roger Hohimer3, Lowell Davis3, Ganesh Acharya5 1 Oulu University Hospital, Obstetrics and Gynecology, Oulu, Finland, 2Oulu University Hospital, Anesthesiology, Oulu, Finland, 3Oregon Health and Science University, Obstetrics and Gynecology, Portland, OR, 4Kuopio University Hospital, Obstetrics and Gynecology, Kuopio, Finland, 5 University Hospital of Northern Norway, Obstetrics and Gynecology, Tromso, Norway
OBJECTIVE: The fetal aortic isthmus (AoI) is the only arterial connection between the fetal right (RV) and left (LV) ventricles. In LV outflow obstruction, blood from the ductus arteriosus flows retrograde across the AoI to supply fetal brain. We hypothesized that in acute ascending aorta (AA) occlusion (AAO), RV cardiac output would increase and maintain normal arterial pressure in the carotid artery. STUDY DESIGN: Nine ewes underwent surgery at 115-135 gestational days (term 145 days) for the placement of a vascular occluder around fetal AA between the aortic valve and brachiocephalic artery. Fetal carotid artery (CA) and jugular vein, and descending aorta (DAo) via femoral artery were cannulated. After a 4-day recovery, fetal heart rate (FHR), right (RVCO) and left (LVCO) ventricular cardiac outputs were measured by ultrasonography. Pulmonary (Qp) volume blood flow and systemic CO (combined cardiac output-Qp) were calculated at baseline, 15 and 60 minutes after AAO, and 15 minutes after release of AAO. Mean arterial blood pressures (mABP) from CA and DAo, central venous (CVP) pressure, and CA pO2 were monitored. RESULTS: All the data are presented as means (SD).* p⬍0.05, compared with baseline. CONCLUSION: In fetal sheep, acute occlusion of AA leads to increased RV cardiac output and decreased LV and systemic cardiac outputs, and pulmonary volume blood flow. Fetal arterial blood pressure in the descending aorta is maintained. However, carotid artery blood pressure decreases during AA occlusion. Our results suggest that, at least in acute conditions, retrograde blood flow shunting across AoI is not able to maintain normal cerebral perfusion pressure.
Supplement to JANUARY 2013 American Journal of Obstetrics & Gynecology
S99
Clinical Obstetrics, Epidemiology, Fetus, Medical-Surgical Complications, Neonatology, Physiology/Endocrinology, Prematurity
CONCLUSION: Our results, in a large cohort of healthy, non-diabetic
women have shown that insulin resistance, even at levels below those diagnostic of gestational diabetes, is associated with maternal and fetal inflammatory response. These findings have important implications for defining the pathway for fetal programming of later metabolic syndrome and childhood obesity.
211 Cardiotonic steroids induce an anti-angiogenic profile in first trimester cytotrophoblast cells Jessica Ehrig1, Kelsey Kelso1, Russell Fothergill1, Steven Allen1, Richard Jones1, Thomas Kuehl1, Mohammad Uddin1 1 Scott & White Memorial Hospital / Texas A&M Health Science Center College of Medicine, Department of Obstetrics & Gynecology, Temple, TX
OBJECTIVE: Preeclampsia (preE), a hypertensive disorder unique to pregnancy, is characterized by abnormal placentation. Our investigative team has demonstrated that marinobufagenin (MBG), one of the cardiotonic steroids (CTSs), inhibits these critical steps for normal placental development: proliferation, migration and invasion of cytotrophoblast (CTB) cells. The aim of this study is to determine whether CTSs induce anti-angiogenic effects in CTB cells. STUDY DESIGN: Cells from the human extravillous CTB cell line Sw.71, derived from first trimester chorionic villus tissue, were incubated with 0.1, 1, 10, and 100 nM of each of three types of CTS (MBG, Cinobufatalin and Ouabain) for 72 h. Thereafter, the levels of angiogenic factors, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and anti-angiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEnd) were measured in the cell culture media by commercially available ELISA kits. Additionally, the expression of three CTB receptors, VEGF-1, angiogenic angiotensin type 1 receptor (AT1) and anti-angiogenic angiotensin type 2 receptor (AT2) were assayed using immunoblotting (western blot) in cell lysates. RESULTS: sFlt-1 and sEnd secretion were significantly increased while VEGF and PIGF were decreased in the culture media of CTB cells treated with ⭌1 nM of all three CTSs (*p⬍0.05 for each). The AT2 receptor expression was significantly up-regulated in ⭌ 1 nM CTStreated CTB cells, whereas AT2 and VEGF-1 receptor expressions were down-regulated (*p⬍0.05 in each case). CONCLUSION: Exposure of CTB cells to CTSs induces an anti-angiogenic profile by: (i) up-regulating AT2 receptor expression; (ii) downregulating AT1 and VEGF-1 receptor expression; (iii) increasing secretion of sFlt-1 and sEnd; and (iv) decreasing secretion of VEGF and PlGF.
212 Circulating adipokines in twins and singletons - linking the bridge from plurality to restricted fetal growth Jiga Haas1, Eyal Sivan1, Eyal Schiff1, Yoav Yinon1, Mordechai Dulitzky1, Eran Barzilay1, Rina Hemi2, Clara Pariente2, Hannah Kanety2, Shali Mazaki-Tovi1 1 Sheba Medical Center, Tel-Hashomer, Department of Obstetrics and Gynecology, Ramat Gan, Israel, 2Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Department of Obstetrics and Gynecology, Ramat Gan, Israel
OBJECTIVE: The condensational view is that the uterine milieu is limited in its ability to nurture more than one fetus. Yet, the mechanism(s) by which attenuated twins growth is achieved has eluded elucidation. Adipokines have been implicated in fetal growth and development. The aim of this study is to determine cord blood adiponectin and leptin in twins and singletons. STUDY DESIGN: This is a case-control study included 2 groups of newborns, matched for gestational age and birthweight percentile: 1. singleton (n⫽60) and 2. twins (n⫽44). Adiponectin and leptin were determined in arterial cord blood. Non-parametric and parametric statistical methods were used. RESULTS: Median adiponectin (31.5 vs. 63 g/dL) and leptin (2.5 vs. 5.6 ng/dL) concentrations was lower in twins vs. singletons (p⬍0.001 for both comparisons). Among SGA newborns, median concentra-
Poster Session I
tion of adiponectin (p⫽0.02), but not leptin (p⫽0.1), was lower in twins compared to singleton. Cord blood adiponectin was strongly correlated with gestational age (p⬍0.001, r⫽0.55) and birthweight (p⬍0.001, r⫽0.59), as was cord blood leptin (gestational age: p⫽0.005, r⫽0.27; birthweight: p⬍0.001, r⫽0.44). Regression analysis revealed that plurality, gestational age and birthweight were significantly and independently associated with cord blood adiponectin concentrations after adjustment for maternal BMI, age and gender. Similar regression model did not revealed association between plurality and cord blood leptin concentrations. CONCLUSION: Twins pregnancies are associated with lower cord blood concentrations of adiponectin, but not leptin, compared with singleton gestations. These findings suggest that alterations in adiponectin concentrations may provide a molecular mechanism to account for the growth disparity between twins and singleton. These findings support the concept that adipokines, particularly adiponectin may play a role in the complex and intriguing process of fetal growth.
213 Acute ascending aorta occlusion leads to decreased cerebral perfusion pressure in a fetal sheep Heikki Huhta1, Juha Räsänen4, Juulia Junno1, Mervi Haapsamo1, Tiina Erkinaro2, Roger Hohimer3, Lowell Davis3, Ganesh Acharya5 1 Oulu University Hospital, Obstetrics and Gynecology, Oulu, Finland, 2Oulu University Hospital, Anesthesiology, Oulu, Finland, 3Oregon Health and Science University, Obstetrics and Gynecology, Portland, OR, 4Kuopio University Hospital, Obstetrics and Gynecology, Kuopio, Finland, 5 University Hospital of Northern Norway, Obstetrics and Gynecology, Tromso, Norway
OBJECTIVE: The fetal aortic isthmus (AoI) is the only arterial connection between the fetal right (RV) and left (LV) ventricles. In LV outflow obstruction, blood from the ductus arteriosus flows retrograde across the AoI to supply fetal brain. We hypothesized that in acute ascending aorta (AA) occlusion (AAO), RV cardiac output would increase and maintain normal arterial pressure in the carotid artery. STUDY DESIGN: Nine ewes underwent surgery at 115-135 gestational days (term 145 days) for the placement of a vascular occluder around fetal AA between the aortic valve and brachiocephalic artery. Fetal carotid artery (CA) and jugular vein, and descending aorta (DAo) via femoral artery were cannulated. After a 4-day recovery, fetal heart rate (FHR), right (RVCO) and left (LVCO) ventricular cardiac outputs were measured by ultrasonography. Pulmonary (Qp) volume blood flow and systemic CO (combined cardiac output-Qp) were calculated at baseline, 15 and 60 minutes after AAO, and 15 minutes after release of AAO. Mean arterial blood pressures (mABP) from CA and DAo, central venous (CVP) pressure, and CA pO2 were monitored. RESULTS: All the data are presented as means (SD).* p⬍0.05, compared with baseline. CONCLUSION: In fetal sheep, acute occlusion of AA leads to increased RV cardiac output and decreased LV and systemic cardiac outputs, and pulmonary volume blood flow. Fetal arterial blood pressure in the descending aorta is maintained. However, carotid artery blood pressure decreases during AA occlusion. Our results suggest that, at least in acute conditions, retrograde blood flow shunting across AoI is not able to maintain normal cerebral perfusion pressure.
Supplement to JANUARY 2013 American Journal of Obstetrics & Gynecology
S99